CUBICIN Powder for concentrate for solution for injection or infusion Ref.[2700] Active ingredients: Daptomycin

Source: Medicines & Healthcare Products Regulatory Agency (GB)  Revision Year: 2019  Publisher: Merck Sharp & Dohme B.V., Waarderweg 39, 2031 BN Haarlem, The Netherlands

Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Special warnings and precautions for use

General

If a focus of infection other than cSSTI or RIE is identified after initiation of Cubicin therapy consideration should be given to instituting alternative antibacterial therapy that has been demonstrated to be efficacious in the treatment of the specific type of infection(s) present.

Anaphylaxis/hypersensitivity reactions

Anaphylaxis/hypersensitivity reactions have been reported with Cubicin. If an allergic reaction to Cubicin occurs, discontinue use and institute appropriate therapy.

Pneumonia

It has been demonstrated in clinical studies that Cubicin is not effective in the treatment of pneumonia. Cubicin is therefore not indicated for the treatment of pneumonia.

RIE due to Staphylococcus aureus

Clinical data on the use of Cubicin to treat RIE due to Staphylococcus aureus are limited to 19 adult patients (see “Information from clinical trials” in section 5.1). The safety and efficacy of Cubicin in children and adolescents aged below 18 years with right-sided infective endocarditis (RIE) due to Staphylococcus aureus have not been established.

The efficacy of Cubicin in patients with prosthetic valve infections or with left-sided infective endocarditis due to Staphylococcus aureus has not been demonstrated.

Deep-seated infections

Patients with deep-seated infections should receive any required surgical interventions (e.g. debridement, removal of prosthetic devices, valve replacement surgery) without delay.

Enterococcal infections

There is insufficient evidence to be able to draw any conclusions regarding the possible clinical efficacy of Cubicin against infections due to enterococci, including Enterococcus faecalis and Enterococcus faecium. In addition, dose regimens of daptomycin that might be appropriate for the treatment of enterococcal infections, with or without bacteraemia, have not been identified. Failures with daptomycin in the treatment of enterococcal infections that were mostly accompanied by bacteraemia have been reported. In some instances treatment failure has been associated with the selection of organisms with reduced susceptibility or frank resistance to daptomycin (see section 5.1).

Non-susceptible micro-organisms

The use of antibacterials may promote the overgrowth of non-susceptible micro-organisms. If superinfection occurs during therapy, appropriate measures should be taken.

Clostridium difficile-associated diarrhoea

Clostridium difficile-associated diarrhoea (CDAD) has been reported with Cubicin (see section 4.8). If CDAD is suspected or confirmed, Cubicin may need to be discontinued and appropriate treatment instituted as clinically indicated.

Drug/laboratory test interactions

False prolongation of prothrombin time (PT) and elevation of international normalised ratio (INR) have been observed when certain recombinant thromboplastin reagents are utilised for the assay (see also section 4.5).

Creatine phosphokinase and myopathy

Increases in plasma creatine phosphokinase (CPK; MM isoenzyme) levels associated with muscular pains and/or weakness and cases of myositis, myoglobinaemia and rhabdomyolysis have been reported during therapy with Cubicin (see also sections 4.5, 4.8 and 5.3). In clinical studies, marked increases in plasma CPK to > 5x Upper Limit of Normal (ULN) without muscle symptoms occurred more commonly in Cubicin-treated patients (1.9%) than in those that received comparators (0.5%). Therefore, it is recommended that:

  • Plasma CPK should be measured at baseline and at regular intervals (at least once weekly) during therapy in all patients.
  • CPK should be measured more frequently (e.g. every 2-3 days at least during the first two weeks of treatment) in patients who are at higher risk of developing myopathy. For example, patients with any degree of renal impairment (creatinine clearance < 80 ml/min; see also section 4.2), including those on haemodialysis or CAPD, and patients taking other medicinal products known to be associated with myopathy (e.g. HMG-CoA reductase inhibitors, fibrates and ciclosporin).
  • It cannot be ruled out that those patients with CPK greater than 5 times upper limit of normal at baseline may be at increased risk of further increases during daptomycin therapy. This should be taken into account when initiating daptomycin therapy and, if daptomycin is given, these patients should be monitored more frequently than once weekly.
  • Cubicin should not be administered to patients who are taking other medicinal products associated with myopathy unless it is considered that the benefit to the patient outweighs the risk.
  • Patients should be reviewed regularly while on therapy for any signs or symptoms that might represent myopathy.
  • Any patient that develops unexplained muscle pain, tenderness, weakness or cramps should have CPK levels monitored every 2 days. Cubicin should be discontinued in the presence of unexplained muscle symptoms if the CPK level reaches greater than 5 times upper limit of normal.

Peripheral neuropathy

Patients who develop signs or symptoms that might represent a peripheral neuropathy during therapy with Cubicin should be investigated and consideration should be given to discontinuation of daptomycin (see sections 4.8 and 5.3).

Eosinophilic pneumonia

Eosinophilic pneumonia has been reported in patients receiving Cubicin (see section 4.8). In most reported cases associated with Cubicin, patients developed fever, dyspnoea with hypoxic respiratory insufficiency, and diffuse pulmonary infiltrates. The majority of cases occurred after more than 2 weeks of treatment with Cubicin and improved when Cubicin was discontinued and steroid therapy was initiated. Recurrence of eosinophilic pneumonia upon re-exposure has been reported. Patients who develop these signs and symptoms while receiving Cubicin should undergo prompt medical evaluation, including, if appropriate, bronchoalveolar lavage, to exclude other causes (e.g. bacterial infection, fungal infection, parasites, other medicinal products). Cubicin should be discontinued immediately and treatment with systemic steroids should be initiated when appropriate.

Renal impairment

Renal impairment has been reported during treatment with Cubicin. Severe renal impairment may in itself also pre-dispose to elevations in daptomycin levels which may increase the risk of development of myopathy (see above).

An adjustment of Cubicin dose interval is needed for patients whose creatinine clearance is < 30 ml/min (see sections 4.2 and 5.2). The safety and efficacy of the dose interval adjustment have not been evaluated in controlled clinical trials and the recommendation is mainly based on pharmacokinetic modelling data. Cubicin should only be used in such patients when it is considered that the expected clinical benefit outweighs the potential risk.

Caution is advised when administering Cubicin to patients who already have some degree of renal impairment (creatinine clearance <80 ml/min) before commencing therapy with Cubicin. Regular monitoring of renal function is advised (see also section 5.2).

In addition, regular monitoring of renal function is advised during concomitant administration of potentially nephrotoxic agents, regardless of the patient’s pre-existing renal function (see also section 4.5).

The dosage regimen for Cubicin in paediatric patients with renal impairment has not been established.

Obesity

In obese subjects with Body Mass Index (BMI) >40 kg/m² but with creatinine clearance >70 ml/min, the AUC0-∞ daptomycin was significantly increased (mean 42% higher) compared with non-obese matched controls. There is limited information on the safety and efficacy of daptomycin in the very obese and so caution is recommended. However, there is currently no evidence that a dose reduction is required (see section 5.2).

Interaction with other medicinal products and other forms of interaction

Daptomycin undergoes little to no Cytochrome P450 (CYP450)-mediated metabolism. It is unlikely that daptomycin will inhibit or induce the metabolism of medicinal products metabolised by the P450 system.

Interaction studies for Cubicin were performed with aztreonam, tobramycin, warfarin and probenecid. Daptomycin had no effect on the pharmacokinetics of warfarin or probenecid, nor did these medicinal products alter the pharmacokinetics of daptomycin. The pharmacokinetics of daptomycin were not significantly altered by aztreonam.

Although small changes in the pharmacokinetics of daptomycin and tobramycin were observed during coadministration by intravenous infusion over a 30-minute period using a Cubicin dose of 2 mg/kg, the changes were not statistically significant. The interaction between daptomycin and tobramycin with an approved dose of Cubicin is unknown. Caution is warranted when Cubicin is co-administered with tobramycin.

Experience with the concomitant administration of Cubicin and warfarin is limited. Studies of Cubicin with anticoagulants other than warfarin have not been conducted. Anticoagulant activity in patients receiving Cubicin and warfarin should be monitored for the first several days after therapy with Cubicin is initiated.

There is limited experience regarding concomitant administration of daptomycin with other medicinal products that may trigger myopathy (e.g. HMG-CoA reductase inhibitors). However, some cases of marked rises in CPK levels and cases of rhabdomyolysis occurred in patients taking one of these medicinal products at the same time as Cubicin. It is recommended that other medicinal products associated with myopathy should if possible be temporarily discontinued during treatment with Cubicin unless the benefits of concomitant administration outweigh the risk. If co-administration cannot be avoided, CPK levels should be measured more frequently than once weekly and patients should be closely monitored for any signs or symptoms that might represent myopathy. See sections 4.4, 4.8 and 5.3.

Daptomycin is primarily cleared by renal filtration and so plasma levels may be increased during co-administration with medicinal products that reduce renal filtration (e.g. NSAIDs and COX-2 inhibitors). In addition, there is a potential for a pharmacodynamic interaction to occur during co-administration due to additive renal effects. Therefore, caution is advised when daptomycin is co-administered with any other medicinal product known to reduce renal filtration.

During post–marketing surveillance, cases of interference between daptomycin and particular reagents used in some assays of prothrombin time/international normalised ratio (PT/INR) have been reported. This interference led to a false prolongation of PT and elevation of INR. If unexplained abnormalities of PT/INR are observed in patients taking daptomycin, consideration should be given to a possible in vitro interaction with the laboratory test. The possibility of erroneous results may be minimised by drawing samples for PT or INR testing near the time of trough plasma concentrations of daptomycin (see section 4.4).

Fertility, pregnancy and lactation

Pregnancy

No clinical data on pregnancies are available for daptomycin. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3).

Cubicin should not be used during pregnancy unless clearly necessary i.e. only if the expected benefit outweighs the possible risk.

Breast-feeding

In a single human case study, Cubicin was intravenously administered daily for 28 days to a nursing mother at a dose of 500 mg/day, and samples of the patient’s breast milk were collected over a 24-hour period on day 27. The highest measured concentration of daptomycin in the breast milk was 0.045 mcg/ml, which is a low concentration. Therefore, until more experience is gained, breast-feeding should be discontinued when Cubicin is administered to nursing women.

Fertility

No clinical data on fertility are available for daptomycin. Animal studies do not indicate direct or indirect harmful effects with respect to fertility (see section 5.3).

Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed.

On the basis of reported adverse drug reactions, Cubicin is presumed to be unlikely to produce an effect on the ability to drive or use machinery.

Undesirable effects

Summary of the safety profile

In clinical studies, 2,011 subjects received Cubicin. Within these trials, 1,221 subjects received a daily dose of 4 mg/kg, of whom 1,108 were patients and 113 were healthy volunteers; 460 subjects received a daily dose of 6 mg/kg, of whom 304 were patients and 156 were healthy volunteers. Adverse reactions (i.e. considered by the investigator to be possibly, probably, or definitely related to the medicinal product) were reported at similar frequencies for Cubicin and comparator regimens.

The most frequently reported adverse reactions (frequency common (≥1/100 to <1/10)) are: Fungal infections, urinary tract infection, candida infection, anaemia, anxiety, insomnia, dizziness, headache, hypertension, hypotension, gastrointestinal and abdominal pain, nausea, vomiting, constipation, diarrhoea, flatulence, bloating and distension, liver function tests abnormal (increased alanine aminotransferase (ALT), aspartate aminotransferase (AST) or alkaline phosphatase (ALP)), rash, pruritus, limb pain, serum creatine phosphokinase (CPK) increased, infusion site reactions, pyrexia, asthenia.

Less frequently reported, but more serious, adverse reactions include hypersensitivity reactions, eosinophilic pneumonia, drug rash with eosinophilia and systemic symptoms (DRESS), angioedema and rhabdomyolysis.

Tabulated list of adverse reactions

The following adverse reactions were reported during therapy and during follow-up with frequencies corresponding to very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data):

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 1. Adverse reactions from clinical studies and post-marketing reports:

Infections and infestations

Common: Fungal infections, urinary tract infection, candida infection

Uncommon: Fungaemia

Not known*: Clostridium difficile-associated diarrhoea**

Blood and lymphatic system disorders

Common: Anaemia

Uncommon: Thrombocythaemia, eosinophilia, international normalised ratio (INR) increased, leukocytosis

Rare: Prothrombin time (PT) prolonged

Not known*: Thrombocytopaenia

Immune system disorders

Not known*: Hypersensitivity**, manifested by isolated spontaneous reports including, but not limited to angioedema, drug rash with eosinophilia and systemic symptoms (DRESS), pulmonary eosinophilia, vesicobullous rash with mucous membrane involvement and sensation of oropharyngeal swelling, anaphylaxis**, infusion reactions including the following symptoms: tachycardia, wheezing, pyrexia, rigors, systemic flushing, vertigo, syncope and metallic taste

Metabolism and nutrition disorders

Uncommon: Decreased appetite, hyperglycaemia, electrolyte imbalance

Psychiatric disorders

Common: Anxiety, insomnia

Nervous system disorders

Common: Dizziness, headache

Uncommon: Paraesthesia, taste disorder, tremor, eye irritation

Not known*: Peripheral neuropathy**

Ear and labyrinth disorders

Uncommon: Vertigo

Cardiac disorders

Uncommon: Supraventricular tachycardia, extrasystole

Vascular disorders

Common: Hypertension, hypotension

Uncommon: Flushes

Respiratory, thoracic and mediastinal disorders

Not known*: Eosinophilic pneumonia1**, cough

Gastrointestinal disorders

Common: Gastrointestinal and abdominal pain, nausea, vomiting, constipation, diarrhoea, flatulence, bloating and distension

Uncommon: Dyspepsia, glossitis

Hepatobiliary disorders

Common: Liver function tests abnormal2 (increased alanine aminotransferase (ALT), aspartate aminotransferase (AST) or alkaline phosphatase (ALP))

Rare: Jaundice

Skin and subcutaneous tissue disorders

Common: Rash, pruritus

Uncommon: Urticaria

Not known*: Acute generalised exanthematous pustulosis

Musculoskeletal and connective tissue disorders

Common: Limb pain, serum creatine phosphokinase (CPK)2 increased

Uncommon: Myositis, increased myoglobin, muscular weakness, muscle pain, arthralgia, serum lactate dehydrogenase (LDH) increased, muscle cramps

Not known*: Rhabdomyolysis3 **

Renal and urinary disorders

Uncommon: Renal impairment, including renal failure and renal insufficiency, serum creatinine increased

Reproductive system and breast disorders

Uncommon: Vaginitis

General disorders and administration site conditions

Common: Infusion site reactions, pyrexia, asthenia

Uncommon: Fatigue, pain

* Based on post-marketing reports. Since these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency which is therefore categorised as not known.
** See section 4.4.
1 While the exact incidence of eosinophilic pneumonia associated with daptomycin is unknown, to date the reporting rate of spontaneous reports is very low (<1/10,000).
2 In some cases of myopathy involving raised CPK and muscle symptoms, the patients also presented with elevated transaminases. These transaminase increases were likely to be related to the skeletal muscle effects. The majority of transaminase elevations were of Grade 1-3 toxicity and resolved upon discontinuation of treatment.
3 When clinical information on the patients was available to make a judgement, approximately 50% of the cases occurred in patients with pre-existing renal impairment, or in those receiving concomitant medicinal products known to cause rhabdomyolysis.

The safety data for the administration of daptomycin via 2-minute intravenous injection are derived from two pharmacokinetic studies in healthy volunteers. Based on these study results, both methods of daptomycin administration, the 2-minute intravenous injection and the 30-minute intravenous infusion, had a similar safety and tolerability profile. There was no relevant difference in local tolerability or in the nature and frequency of adverse reactions.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Incompatibilities

Cubicin is not physically or chemically compatible with glucose-containing solutions. This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

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